SummaryThe world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age-related dysfunction of the immune system resulting from low-grade chronic inflammation known as 'inflamm-ageing'. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life-threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age-related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age-specific therapies to address lung infections in such a vulnerable population.

Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4+ T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4+ T cells has not been directly examined.Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4+ T cell differentiation and function later in life.Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4+ T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4+ T-cell responses resulted from direct effects of developmental TCDD exposure on CD4+ T cells.Results: Developmental exposure skewed CD4+ T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4+ T cells and a reduced frequency of conventional CD4+ effector-cell subsets. However, there was an increase in regulatory CD4+ T cells. Direct effects of AhR activation on CD4+ T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD.Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4+ T cells in adult C57BL/6 mice.Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110

The aryl hydrocarbon receptor (AHR) offers a compelling target to modulate the immune system. AHR agonists alter adaptive immune responses, but the consequences differ across studies. We report here the comparison of four agents representing different sources of AHR ligands in mice infected with influenza A virus (IAV): TCDD, prototype exogenous AHR agonist; PCB126, pollutant with documented human exposure; ITE, novel pharmaceutical; and FICZ, degradation product of tryptophan. All four compounds diminished virus-specific IgM levels and increased the proportion of regulatory T cells. TCDD, PCB126 and ITE, but not FICZ, reduced virus-specific IgG levels and CD8 + T cell responses. Similarly, ITE, PCB126, and TCDD reduced Th1 and Tfh cells, whereas FICZ increased their frequency. In Cyp1a1-deficient mice, all compounds, including FICZ, reduced the response to IAV. Conditional Ahr knockout mice revealed that all four compounds require AHR within hematopoietic cells. Thus, differences in the immune response to IAV likely reflect variances in quality, magnitude, and duration of AHR signaling. This indicates that binding affinity and metabolism may be stronger predictors of immune effects than a compound's source of origin, and that harnessing AHR will require finding a balance between dampening immune-mediated pathologies and maintaining sufficient host defenses against infection.There is considerable evidence that signaling through the aryl hydrocarbon receptor (AHR) alters the course of adaptive immune responses in a manner that can be protective or detrimental. Adaptive immune responses underlie host protection from pathogens, but when improperly controlled they contribute to numerous diseases. The AHR's remarkable capacity to modulate T cell responses has been demonstrated in autoimmune diseases 1-5 , allergic inflammation 6,7 , and inflammatory bowel diseases [8][9][10] . Yet, these reports also suggest that different AHR ligands may bias adaptive immune responses in opposite directions, and that exposure to the same ligand can worsen or improve pathology in different disease models 1,2,11 . While these issues remain to be resolved, the ability of the AHR to modulate T cell differentiation and T cell-dependent immune responses has generated enthusiasm about targeting therapeutic agents at the AHR in order to modulate the progression of a large spectrum of immune-mediated diseases 12,13 .Yet, there is another aspect of AHR immunobiology that has direct bearing on the potential success of new strategies to use AHR ligands as treatment modalities: the impact on host responses to infection. Several reports demonstrate the importance of AHR in sensing microbes, including pathogenic and commensal bacteria, mycobacteria, and fungi [14][15][16][17] . Epidemiological studies show strong correlations between exposure to anthropogenically-derived AHR ligands from the environment and increased incidence and severity of respiratory infections, most notably viral infections 18,19 . These observations have been extended with a...

SYNOPSIS With the coming of the “Silver Tsunami,” expanding our knowledge about how a variety of intrinsic and extrinsic factors affect the immune system in the elderly is both timely and of immediate clinical need. It is clear that the global population is increasing in age. By the year 2030, over 20% of the population of the United States will be over 65 years of age. In this chapter, we will focus on how advanced age alters the immune systems and how this, in turn, modulates the ability of the aging lung to deal with the infectious challenges from both the outside world and from within the host.

Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR-accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T-cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared with males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life.

The global population is aging: in 2010, 8% of the population was older than 65 y, and that is expected to double to 16% by 2050. With advanced age comes a heightened prevalence of chronic diseases. Moreover, elderly humans fair worse after acute diseases, namely infection, leading to higher rates of infection-mediated mortality. Advanced age alters many aspects of both the innate and adaptive immune systems, leading to impaired responses to primary infection and poor development of immunologic memory. An often overlooked, yet increasingly common, behavior in older individuals is alcohol consumption. In fact, it has been estimated that >40% of older adults consume alcohol, and evidence reveals that >10% of this group is drinking more than the recommended limit by the National Institute on Alcohol Abuse and Alcoholism. Alcohol consumption, at any level, alters host immune responses, including changes in the number, phenotype, and function of innate and adaptive immune cells. Thus, understanding the effect of alcohol ingestion on the immune system of older individuals, who are already less capable of combating infection, merits further study. However, there is currently almost nothing known about how drinking alters innate immunity in older subjects, despite innate immune cells being critical for host defense, resolution of inflammation, and maintenance of immune homeostasis. Here, we review the effects of aging and alcohol consumption on innate immune cells independently and highlight the few studies that have examined the effects of alcohol ingestion in aged individuals.

Boule LA, Winans B, Lambert K, Vorderstrasse BA, Topham DJ, Pavelka MS Jr, Lawrence BP. Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4ϩ T-cell response to viral infection.

SummaryRecent studies have linked health fates of children to environmental exposures of their great grandparents. However, few studies have considered whether ancestral exposures influence immune function across generations. Here, we report transgenerational inheritance of altered T cell responses resulting from maternal (F0) exposure to the aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since F0 exposure to TCDD has been linked to transgenerational transmission of reproductive problems, we asked whether maternal TCDD exposure also caused transgenerational changes in immune function. F0 exposure caused transgenerational effects on the CD8+ T cell response to influenza virus infection in females but not in males. Outcrosses showed changes were passed through both parental lineages. These data demonstrate that F0 exposure to an aryl hydrocarbon receptor (AHR) agonist causes durable changes to immune responses that can affect subsequent generations. This has broad implications for understanding how the environment of prior generations shapes susceptibility to pathogens and antiviral immunity in later generations.